Paracrine signaling by glial cell–derived triiodothyronine activates neuronal gene expression in the rodent brain and human cells
Beatriz C.G. Freitas, … , Ronald M. Lechan, Antonio C. Bianco
Beatriz C.G. Freitas, … , Ronald M. Lechan, Antonio C. Bianco
Published May 10, 2010
Citation Information: J Clin Invest. 2010;120(6):2206-2217. https://doi.org/10.1172/JCI41977.
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Research Article Endocrinology

Paracrine signaling by glial cell–derived triiodothyronine activates neuronal gene expression in the rodent brain and human cells

Abstract

Hypothyroidism in humans is characterized by severe neurological consequences that are often irreversible, highlighting the critical role of thyroid hormone (TH) in the brain. Despite this, not much is known about the signaling pathways that control TH action in the brain. What is known is that the prohormone thyroxine (T4) is converted to the active hormone triiodothyronine (T3) by type 2 deiodinase (D2) and that this occurs in astrocytes, while TH receptors and type 3 deiodinase (D3), which inactivates T3, are found in adjacent neurons. Here, we modeled TH action in the brain using an in vitro coculture system of D2-expressing H4 human glioma cells and D3-expressing SK-N-AS human neuroblastoma cells. We found that glial cell D2 activity resulted in increased T3 production, which acted in a paracrine fashion to induce T3-responsive genes, including ectonucleotide pyrophosphatase/phosphodiesterase 2 (ENPP2), in the cocultured neurons. D3 activity in the neurons modulated these effects. Furthermore, this paracrine pathway was regulated by signals such as hypoxia, hedgehog signaling, and LPS-induced inflammation, as evidenced both in the in vitro coculture system and in in vivo rat models of brain ischemia and mouse models of inflammation. This study therefore presents what we believe to be the first direct evidence for a paracrine loop linking glial D2 activity to TH receptors in neurons, thereby identifying deiodinases as potential control points for the regulation of TH signaling in the brain during health and disease.

Authors

Beatriz C.G. Freitas, Balázs Gereben, Melany Castillo, Imre Kalló, Anikó Zeöld, Péter Egri, Zsolt Liposits, Ann Marie Zavacki, Rui M.B. Maciel, Sungro Jo, Praful Singru, Edith Sanchez, Ronald M. Lechan, Antonio C. Bianco

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Figure 3

Hypoxia induces D3 in the brain and decreases TH signaling.

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Hypoxia induces D3 in the brain and decreases TH signaling. D3 IR using ...
D3 IR using the NBP1-5767 α-D3 antiserum in coronal brain sections of male rat stroke model: (A–C) sham operated; (D–I) unilateral MCAO for 1 hour. (A) Low-power micrograph of a coronal brain section (bregma, –3.3 mm) shows widespread distribution of D3 IR in sham. The intensity of D3 staining exhibits regional variations; in the cerebral cortex and hippocampus of sham-operated controls, the IR is moderate and localized primarily to the apical dendrite (arrowheads) and the perikaryon (arrows) of pyramidal cells (B), whereas it is intense in the axons (arrowheads) and cell bodies of the hypothalamic preoptic area (C). (D–E) Ischemia resulted in an increased D3 IR on the ipsilateral side (MCAO-il) compared with the control contralateral side (MCAO-cl) of the occlusion shown for both the primary somatosensory cortex (E versus D) and the hippocampus (G versus F). (H–I) Preincubation of the primary antibody with the peptide antigen (PEP) used for immunization resulted in complete loss of immunostaining demonstrated in neighboring hypothalamic sections. Scale bars: 3 mm (A); 50 μm (B); 100 μm (C); 1 mm (D–I). DG, dentate gyrus; POA, preoptic area; S1, primary somatosensory cortex; V, third ventricle.